As described, for example, by M. Packer et al., in the article "Effect of Oral Milrinone on Mortality in Severe Chronic Heart Failure," published in the New England Journal of Medicine 325(21): pp. 1468-1475 (1991), it is well known that patients with CHF generally have impaired cardiac contractility. Milrinone, or 1,6-dihydro-2-methyl-6-oxo-(3,4'-bi-pyridine)-5-carbonitrile, is a known selective PDE inhibitor with vasodilating and positive inotropic activity (see, e.g., The Merck Index, 12th ed., Merck & Co., Inc., p. 1060 (1996)) and enhances cardiac contractility see, e.g., M. Packer et al. referenced-above).
Packer et al. also disclosed in the article referenced-above that Milrinone enhances cardiac contractility by increasing intracellular levels of the know "second messenger" (responds to hormones which are considered the "first messengers") cyclic adenosine 3',5'-monophosphate ("cAMP").
As would be understood by those of skill in the relevant art, intracellular levels of CAMP may be increased by either increasing the synthesis of cAMP or decreasing its deactivation or degradation. As described in, e.g., The Merck Index referenced-above at page 456, cAMP is produced from adenosine triphosphate ("ATP") by adenylate cyclase and deactivated or degraded by cyclic nucleotide PDEs which convert cAMP to 5'-adenylic acid. Beta-adrenergic agonists provide an increase in cAMP levels while PDEs provide a decrease in cAMP levels.
M. D. Feldman et al., in an article published in Circulation 75: pp. 331-9 (1987), reported pharmacological data which showed that deficient production of cAMP in patients with end-stage heart failure caused contractile dysfunction. However, as cautioned by Packer et al. in the article referenced-above, some positive inotropic agents, e.g., certain beta-adrenergic agonists and phosphodiesterase inhibitors, which increase the intracellular concentration of cAMP have been shown to increase mortality in patients with chronic heart failure.
It is accepted by those of skill in the art that distinct classes of PDEs exist. Consequently, selective inhibition of these distinct PDEs has led to improved drug therapy. For example, as described by M. W. Verghese et al., in an article published in the Journal of Molecular & Cellular Cardiology 12 (Suppl. II): S61 (1989) and by S. R. O'Donnell et al., in an article published in 37 Birkhauser-Vedag (1988), inhibition of PDE Type IV inhibits the release of inflammatory mediators and relaxes airway smooth muscle, respectively. Hence, as would be appreciated by those of skill, compounds that inhibit PDE Type IV, but have poor activity against other PDE types, inhibit the release of inflammatory mediators and relax airway smooth muscle without causing undesirable cardiovascular or anti-platelet effects generally associated with the inhibition of non-Type IV PDEs.
As is well known, for example, as described in The Merck Index referenced-above at pages 1672-1673, TNF is a pluripotent cytokine which is produced by, e.g., activated macrophages and human vascular smooth muscle cells, as part of the cellular immune response. As appreciated by those of skill in the relevant art, TNF, or cachetin, is involved in many infectious and auto-immune diseases, and is the central mediator of the inflammatory response seen in sepsis and septic shock.
Further, as is also known, as described by K. Doyama et al., in an article published in the International Journal of Cardiology 54: pp. 217-225 (1996), elevated circulating levels of TNF have been reported in patients with various diseases such as, for example, cancer, infectious and inflammatory disorders, and various cardiac diseases, e.g., acute myocardial infarction, myocarditis, and CHF secondary to dilated cardiomyopathy or ischemic heart disease. Moreover, Doyoma et al. also describes in the article referenced-above that TNF depresses cardiac contractility.
The present invention relates to novel methods and pharmaceutical compositions for treating CHF in mammals, especially humans, with or which comprise, respectively, a compound which inhibits PDE type IV and the production of TNF, such as, for example, a substituted indazole derivative.